A REDOX-BASED O2 SENSOR IN RAT PULMONARY VASCULATURE
A REDOX-BASED O2 SENSOR IN RAT PULMONARY VASCULATURE
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DOI：
10.1161/01.res.73.6.1100
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发表时间：
1993-12-01
影响因子：
20.1
通讯作者：
WEIR, EK
中科院分区：
文献类型：
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作者：
ARCHER, SL;HUANG, J;WEIR, EK
缺氧性肺血管收缩（HPV）的效应机制涉及K+通道抑制和随后的膜去极化。目前尚不清楚低氧如何调节K+通道活性。缺氧和线粒体电子传递链（ETC）抑制剂对代谢和血管张力的类似作用表明了共同的作用机制。ETC抑制剂和缺氧可能会改变细胞的氧化还原状态，造成积累的电子供体从克雷布斯循环和减少生产的活化O2物种（AOS）的ETC。我们假设，这种转变向一个更减少氧化还原状态elaphenic血管收缩抑制K+通道。肺动脉压和AOS，同时使用增强化学发光测量，在隔离灌注大鼠肺暴露于缺氧，近端ETC抑制剂（鱼藤酮和抗霉素A），和远端ETC抑制剂（氰化物）进行了研究。膜片钳全细胞钾电流的测量新鲜分离的大鼠肺血管平滑肌细胞在暴露于缺氧和ETC抑制剂。缺氧、鱼藤酮和抗霉素A降低了肺化学发光（分别为-62+/-12、-46+/-7和-148+/-36计数/0.1 s），随后增加了肺动脉压（分别为+14+/-2、+13+/-3和+21+/-3 mm Hg）。这些药物可逆地抑制肺血管平滑肌细胞的外向，ATP-非依赖性，K+电流。抗霉素A和鱼藤酮消除了随后的HPV。相反，氰化物增加AOS，不改变K+电流或抑制HPV。鱼藤酮、抗霉素A和缺氧的最初作用是氧化还原状态的改变（明显表现为AOS产生的减少）。这与ATP非依赖性K+通道的可逆抑制和血管收缩有关。这些发现与肺血管系统中存在基于氧化还原的O2传感器一致。
The effector mechanism of hypoxic pulmonary vasoconstriction (HPV) involves K+ channel inhibition with subsequent membrane depolarization. It remains uncertain how hypoxia modulates K+ channel activity. The similar effects of hypoxia and mitochondrial electron transport chain (ETC) inhibitors on metabolism and vascular tone suggest a common mechanism of action. ETC inhibitors and hypoxia may alter cell redox status by causing an accumulation of electron donors from the Krebs cycle and by decreasing the production of activated O2 species (AOS) by the ETC. We hypothesized that this shift toward a more reduced redox state elicits vasoconstriction by inhibition of K+ channels. Pulmonary artery pressure and AOS, measured simultaneously using enhanced chemiluminescence, were studied in isolated perfused rat lungs during exposure to hypoxia, proximal ETC inhibitors (rotenone and antimycin A), and a distal ETC inhibitor (cyanide). Patch-clamp measurements of whole-cell K+ currents were made on freshly isolated rat pulmonary vascular smooth muscle cells during exposure to hypoxia and ETC inhibitors. Hypoxia, rotenone, and antimycin A decreased lung chemiluminescence (-62+/-12, -46+/-7, and -148+/-36 counts/0.1 s, respectively) and subsequently increased pulmonary artery pressure (+14+/-2, +13+/-3, and +21+/-3 mm Hg, respectively). These agents reversibly inhibited an outward, ATP-independent, K+ current in pulmonary vascular smooth muscle cells. Antimycin A and rotenone abolished subsequent HPV. In contrast, cyanide increased AOS and did not alter K+ currents or inhibit HPV. The initial effect of rotenone, antimycin A, and hypoxia was a change in redox status (evident as a decrease in production of AOS). This was associated with the reversible inhibition of an ATP-independent K+ channel and vasoconstriction. These findings are consistent with the existence of a redox-based 02 sensor in the pulmonary vasculature.